Principal Investigator/Program Director (Last, First, Middle): Jiang, Huabei /Yang, Lily About 20% of breast cancers have a distinct signature of estrogen receptor (ER), progesterone receptor (PR) and Her-2/Neu negative. Over 60% of triple negative breast cancer (TNBC) are highly resistant to chemotherapy and have a poor prognosis. More than 50% of the TNBC patients with drug resistant residual tumors after pre-operative chemotherapy developed local and distant recurrent tumor within three years after surgery and most of them died due to tumor recurrence. This unmet clinical challenge underscores an urgent need for novel approaches for effective treatment of drug resistant TNBCs. One of the approaches that may have the most impact is to develop specific and sensitive image-guided surgery to completely remove small drug resistant tumor lesions and tumor cell involved lymph nodes. We hypothesize that a novel multimodal approach that integrates photoacoustic tomography (PAT) and fluorescence molecular tomography (FMT) in combination with multiplexed tumor biomarker targeted imaging probes can most accurately detect small drug resistant breast tumors and tumor involved lymph nodes in 3D at the microns resolution scale, thus serving as an ideal guidance for surgery of breast cancer. This first ever integrated PAT and FMT device will allow us to three-dimensionally detect small tumors (~30m) at a depth of ~3cm, which are previously unachievable. The goal of this proposal is to advance this cutting-edge imaging technology to engineer a multimodal approach that integrates PAT and FMT into a single endoscope for optimized 3D detection of breast cancer through the use of microelectromechanical systems (MEMS). In particular, we will use multiplexed ?smart? nanoprobes that are targeted to cellular receptors that are highly expressed in TNBC cancer cells, especially aggressive drug resistant cells, such as urokinase plasminogen activator receptor (uPAR) and insulin-like growth factor 1 receptor (IGF-1R) to realize multiplexed specific and sensitive molecular imaging of heterogeneous TNBC cells. A marked pathological feature of TNBC is the presence of extensive tumor stroma expressing high levels of uPAR and IGF1R. Targeting those two receptors further enhances the sensitivity of detection of small tumors (< 1 mm) with poor tumor vessels. Beyond image-guided surgery of breast cancer, we anticipate the technology to be much more broadly applicable to other pressing healthcare problems such as endoscopic detection of esophageal, colon, pancreatic and prostate cancers. This application has put together a truly multi- disciplinary research team involving investigators in imaging, MEMS, probe synthesis, cancer biology, and surgical oncology. With a long-term goal of translating the proposed technology into a clinical application, we propose to complete the following specific aims: (1) To develop a MEMS-based photoacoustic tomography system for intraoperative tumor imaging in real time; (2) To develop a MEMS based multi-modal PAT/FMT system for intraoperative tumor imaging in real time; (3) To validate and optimize the MEMS-PAT and MEMS- PAT/FMT systems using phantom and in vivo experiments; and (4) To determine sensitivity and specificity of PAT and PAT/FMT imaging using the multiplexed targeted imaging probes and evaluate the efficacy of in vivo PAT- and PAT/FMT-guided surgery in two orthotopic human TNBC patient tissue derived tumor xenograft (PDX) models in nude mice.